This K08 application requests support for a MCSDA focusing on the role of neurogenesis in the therapeutic mechanisms of antidepressants. Recent evidence suggests that, beyond neurotransmitter effects, antidepressant treatments impact on signaling and transduction pathways, resulting in structural and functional changes in specific brain regions. All classes of antidepressants, as well as mood stabilizers and environmental enrichment, enhance neuronal proliferation in rodent hippocampus. In contrast, social stress and drugs of abuse appear to blunt proliferation. While the functional significance of neurogenesis is unknown, this pattern of enhancement and suppression and the delayed onset of action of most antidepressants have raised the possibility that neurogenesis is a key factor in the neurobiological cascade that ameliorates depressive states. However, the evidence linking neurogenesis and antidepressant action is largely circumstantial and comes mostly from work with rodents or tree shrews. Through the study of adult Old World monkeys, who have strong neurobiological and behavioral similarities to humans, the candidate will embark on a training and research program designed explicitly to bridge this gap in knowledge. The Training Plan broadens the candidate's knowledge in specific domains: (1) basic science with a focus on immunohistology and neuroanatomy; (2) animal behavior focused on nonhuman primate models of depression and anxiety; (3) molecular-cellular theories and research on antidepressant mechanisms; (4) experimental design, biostatistics, and ethics. Implementation of the training and research components will be mentored by Dr. Harold A. Sackeim, who is joined by an eminent group of scientists serving as the candidate's preceptors and science advisors. The Research Plan concentrates on determining whether enhanced neurogenesis is necessary for antidepressant effects and is framed around the question: Does blocking neurogenesis negate the antidepressant effects of potent interventions? Addressing this issue will require the development of new skills and the conduct of carefully designed experiments over three interim steps. These steps will validate a credible model of mood disturbance that is reliably reversed by antidepressants; demonstrate that fluoxetine stimulates neurogenesis in the adult monkey, as ECS did in the applicant's pilot studies; and validate a method that specifically blocks hippocampal neurogenesis without evidence of damage in adjacent or distal mature neurons. The candidate will then combine these tools to determine if blocking neurogenesis eliminates the "therapeutic action" of fluoxetine in non-human primates. The applicant's training and commitment to clinical psychiatry, his expanding neuroscience background, the scientific and educational resources at Columbia, and the invaluable access to the nonhuman primate colony at SUNY Downstate provides a unique foundation for this proposal. [unreadable] [unreadable]